title: Multi-copper oxidases and human iron metabolism.
abstract: Multi-copper oxidases (MCOs) are a small group of enzymes that oxidize their substrate with the concomitant reduction of dioxygen to two water molecules. Generally, multi-copper oxidases are promiscuous with regards to their reducing substrates and are capable of performing various functions in different species. To date, three multi-copper oxidases have been detected in humans--ceruloplasmin, hephaestin and zyklopen. Each of these enzymes has a high specificity towards iron with the resulting ferroxidase activity being associated with ferroportin, the only known iron exporter protein in humans. Ferroportin exports iron as Fe(2+), but transferrin, the major iron transporter protein of blood, can bind only Fe(3+) effectively. Iron oxidation in enterocytes is mediated mainly by hephaestin thus allowing dietary iron to enter the bloodstream. Zyklopen is involved in iron efflux from placental trophoblasts during iron transfer from mother to fetus. Release of iron from the liver relies on ferroportin and the ferroxidase activity of ceruloplasmin which is found in blood in a soluble form. Ceruloplasmin, hephaestin and zyklopen show distinctive expression patterns and have unique mechanisms for regulating their expression. These features of human multi-copper ferroxidases can serve as a basis for the precise control of iron efflux in different tissues. In this manuscript, we review the biochemical and biological properties of the three human MCOs and discuss their potential roles in human iron homeostasis.
authors.affiliation: Department of Cellular and Physiological Sciences, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T1Z3, Canada. ganna.vashchenko@gmail.com
authors.forename: Ganna
authors.initials: G
authors.lastname: Vashchenko
authors.forename: Ross T A
authors.initials: RT
authors.lastname: MacGillivray
mesh_terms: D000042:Absorption; D027682:Cation Transport Proteins / Q000378:metabolism; D002570:Ceruloplasmin / Q000378:metabolism; D003300:Copper / Q000378:metabolism; D020895:Enterocytes / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D007501:Iron / Q000097:blood / Q000493:pharmacokinetics*; D008565:Membrane Proteins / Q000378:metabolism; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism*; D011487:Protein Conformation; D017382:Reactive Oxygen Species / Q000378:metabolism; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; C492164:HEPH protein, human; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D000098742:Ferroportin; D003300:Copper; D007501:Iron; D010088:Oxidoreductases; C024748:copper oxidase; D002570:Ceruloplasmin